Disrupting tRNA in Bacteria – A Way to Fight Antibiotic Resistant Microbes

Researchers have found a new way by creating a defect in tRNA molecules, thus, weaken the bacterial defense system against antibiotics!

For several reasons, antibiotics that previously were effective against bacteria, no longer work. Misuse and overuse of antibiotics mean they are losing their power. And the more they are used, the more chance bacteria evolve to resist them.

Currently, antibiotic resistance is a growing epidemic and if not resolved could result in 10 million deaths each year by 2050. Moreover, annually MDRs caused 23,000 Americans death, and the number is dramatically increasing.

Today, the search for new antibiotics is the most important goals of our time. However, unfortunately, bacteria again become resistant against most of them.

Therefore, to stop this evolution, scientists must think outside the box and looking for new therapeutics’ strategies to solve an antibiotics-resistant problem.

Video: Antibiotic-resistance explained

Researchers from Thomas Jefferson University

Recently, a team of researchers at the Thomas Jefferson University developed a new therapy that weakens bacterial defense system. And especially against gram-negative bacteria that include E. coli and Salmonella – a class of antibiotics resistance bugs. The report was published in Cell System entitled “ tRNA methylation is a Global Determination of Bacterial Multi-drug Resistance.”

The gram-negative bacteria can be tricky to kill as they got a unique advantage against antibiotics due to their two-pronged defense system – two-layered cell membrane that inhibits the antibiotics from entering the cell. Moreover, it can also pump it out of the cell if entered by anyway. The researchers at Jefferson think they might have found a breakthrough against these defensive strategies.

The key lies in tRNA molecules that play a vital role in protein synthesis by decoding mRNA and assisting the rRNA in building up proteins. However, bacteria have got a different mechanism in which a methyl group attaches with the tRNA. Hou’s team used this as a therapeutic strategy against MDRs. They cut off this methyl group from tRNA and found that the protein synthesis was either inhibited or non-functional proteins were formed.

“We showed that interfering with a transfer RNA (tRNA) molecule, in a way that is unique to bacteria, cripples the bacterial cell’s ability to make membrane proteins required for the drug barrier and efflux activity,” said the senior author of the work, Ya-Ming Hou, Ph.D., a Professor of Biochemistry at the Sidney Kimmel Medical College at Jefferson (Philadelphia University + Thomas Jefferson University).

Ya-Ming Hou, Ph.D. senior author of the work.

They found that the adhesion of the methyl group to the tRNA is the primary factor in the bacterial resistance to antibiotics. To prove their hypothesis, they engineered strains of Salmonella and E. coli that has defective tRNA. And surprisingly the bacteria were not able to show the antibiotic-resistant behavior. Moreover, the strains also couldn’t pump toxic molecules outside the cell. And were more vulnerable to the antibiotics to perforate its cell wall and damage the cell.

“Speed of killing is important in antibiotics,” said Hou. “The longer it takes for bacteria to die from antibiotics, the more likely they are to develop resistance.”

Some pharmaceutical companies have already created drugs that could demethylate the tRNA and interfere with bacterial protein synthesis. But those drugs were ineffective as they couldn’t invade the cell and pass the cell wall barrier. Therefore, there are challenges in producing such type of drugs.

“First, we need to formulate the inhibitors in such a way as to be able to enter the cell more effectively,” noted Hou. “Then, combining these inhibitors with traditional antibiotics to kill bacteria faster and reduce the likelihood of antibiotic resistance.”